LAUSR

Significance The question of how the brain links behavioral and biological features of defensive stress responses has remained elusive. Here, we show that active stress-coping behavior in rats is associated with activity increases along a caudal medial prefrontal cortex–midbrain periaqueductal gray circuit. Optogenetic manipulations of this pathway bidirectionally modulated active coping behavior. However, under more aversive conditions that provoked behavioral passivity and exaggerated stress-hormone responses, excitation of this same pathway significantly reduced each of these response features. These results highlight a neural circuit that may redirect multiple aspects of the organism’s defensive repertoire away from passive coping and may be of importance for understanding how activated neural systems promote stress resilience.